EP3560922A1 - Process for preparation of (4s) - 4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide by racemate resoution through diastereomeric tartaric acid - Google Patents

Abstract

The present invention relates to a new and improved process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxamide amide of the formula (I) and the preparation of the enantiomer (Ia) by a racemate resolution with chiral substituted tartaric acid esters of the general formulas (IIIa) and (IIIb) Where Ar is a substituted or unsubstituted aromatic or heteroaromatic.

Description

sowie die Herstellung des Enantiomeren (Ia) durch eine Racemat-Spaltung mit chiralen substituierten Weinsäureestern der allgemeinen Formeln (IIIa) und (IIIb)

The present invention relates to a new and improved process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine 3-carboxamide of the formula (I)

and the preparation of the enantiomer (Ia) by a racemate resolution with chiral substituted tartaric acid esters of the general formulas (IIIa) and (IIIb)

Wherein Ar is a substituted or unsubstituted aromatic or heteroaromatic.

Finerenone (I) acts as a non-steroidal antagonist of the mineralcorticoid receptor and can be used as an agent for the prophylaxis and / or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy.

in die Antipoden getrennt werden, da nur der Antipode der Formel (I) aktiv ist.The compound of the formula (I) and its production process are in the WO 2008/104306 and ChemMedChem 2012, 7, 1385 as in WO 2016/016287 A1 described. In order to obtain the compound of formula (I), the racemic mixture of amides (II) must

into the antipodes, since only the antipode of formula (I) is active.

In the published research synthesis ( WO 2008/104306 For this purpose, a specially synthesized chiral phase was used (in-house production) which contained poly ( N- methacryloyl-D-leucine-dicyclopropylmethylamide as a chiral selector.) It was found that the separation can also be carried out on a commercially readily available phase it was the phase Chiralpak AS-V, 20 microns as the eluent, a mixture of methanol / acetonitrile 60:40 was used.Here, the chromatography can be carried out on a commercial chromatographic column, but are preferred with the skilled person known techniques such as SMB (simulated moving bed; G. Paredes, M. Mazotti, Journal of Chromatography A, 1142 (2007): 56-68 ) or Varicol (Computers and Chemical Engineering 27 (2003) 1883-1901 ) used.

Although the SMB separation provides quite good yield and optical purity, the cost and operation of such a plant under GMP conditions is challenging and costly. Also, the chiral phase used in each case is very expensive and has only a limited lifetime and must be replaced in an ongoing production again and again. This is not optimal for production reasons, if not a second system is available, so that a continuous operation is guaranteed, which is associated with additional costs. Furthermore, especially for products that are manufactured on a ton scale, the recovery of the solvent is the time-critical step and requires the purchase of huge falling film evaporators and is associated with the consumption of enormous amounts of energy.

It was therefore the object to seek alternatives for the separation of the enantiomeric mixture, which are significantly cheaper and are to be carried out with conventional pilot plant equipment (stirred tank / insulating apparatus). Such systems traditionally belong to the standard equipment of pharmaceutical manufacturing companies and do not require additional investments. Also, the qualification and validation of batch processes is much easier than with chromatographic methods, which is an additional advantage.

Numerous attempts have been made to work out a separation (variation of chiral organic acid and solvent) using the conventional classical methods for racemate resolution, as shown in Table 1: <B> Table 1: </ b> acid solvent (S) - (+) - 1, 1 -binaphthyl-2,2-diyl hydrogen phosphate methanol (-) - quinic acid ethanol (-) - O, O'-diacetyl-L-tartaric acid 1-propanol (-) - O, O'-dipivaloyl-L-tartaric acid 2-propanol (+) - 3-bromocamphor-10-sulfonic acid 1-butanol (+) - 4-chloro-tartranilic acid isobutanol (+) - 4'-Nitrotartranilic acid 1-pentanol (+) - camphoric cyclohexanol (+) - O-acetyl-L-mandelic acid benzyl alcohol (1R) - (-) - camphor-1-sulfonic acid acetone (1S) - (-) - camphanic ethylene glycol (2R, 3R) - (+) - tartaric acid chlorobenzene (R) - (+) - alpha-methoxy-alpha-trifluoromethylphenylacetic acid dichloromethane (S) - (-) - 2-bromopropionic acid ethyl acetate (S) - (-) - 2-chloropropionic acid dimethylacetamide (S) - (+) - citramalic THF (S) - (+) - mandelic acid toluene Ac-Acid Triple Mix Toluene / ethyl acetate 95: 5 Malic acid (Malicacid) Toluene / ethyl acetate 90:10 chlocyphos Toluene / ethyl acetate 80:20 D - (+) - HPP-mono-acid Toluene / ethyl acetate 50:50 L-glutamic acid Toluene / ethanol 95: 5 L-lactic acid Methanol / water 90:10 menthoxyacetic Methanol / water 80:20 N- (3,5-dinitrobenzoyl) - (R) - (-) - 2-phenylglycine Methanol / water 50:50 N-acetyl-L-leucine Ethyl acetate / MeOH 90:10 N-acetyl-L-Phenylalanine Ethanol / water 90:10 N-Ac-OH-proline Ethanol / water 85:15 naproxen Ethanol / water 80:20 phencyphos Ethanol / water 75:25 Ethanol / water 70:30 Ethanol / water 50:50 Methanol / water 90:10 Methanol / water 80:20 Methanol / water 50:50 1-Propanol / water 80:20 Isopropanol / water 80:20 1-butanol / water 90:10 2-butanol / water 80:20 2-butanol / water 90:10 1-pentanol / water 90:10 Cyclohexanol / water 90:10 Benzyl alcohol / water 90:10 Ethylene glycol / water 80:20

Among other things, experiments were performed with the classical cleavage reagent (+) - tartaric acid.

However, no salt formation was observed in all cases, instead only the racemate precipitates out of the solution. This corresponds essentially to the expectations of the person skilled in the art, which one could have deduced from the pKs value of the molecule (II) that classical racemate resolution by means of diastereomeric salt formation with organic acids should not be possible since the measured pKa value (for the base) is 4.3 and thus nearly eliminates salification so that only salt formation using very strong inorganic or organic mineral acids, such as, for example, chiral sulfonic acids or phosphonic acids, should preferably be possible. According to literature, such as " Handbook of Pharmaceutical Salts - Properties, Selection and Use; by Heinrich Heinrich, Camille G. Wermuth (Eds.); Wiley-VCH, p.166 "the pK-value difference should be at least 3 pK units to allow for stable salt formation, which is indeed found using, for example, cyclic phosphoric ester chlocyphos listed below:"

In the implementation with 3 eq. this cyclic phosphoric acid ester with the racemate (II) gives a diastereomeric salt wherein (I) with an enantiomeric excess of only 44% e.e. is present.

All efforts exceed the enantiomeric excess towards> 99% e.e. to bring were not effective; In addition, Chlocyphos was not commercially available in large quantities, therefore, was looking for other alternatives.

In the reaction with alkyl-substituted tartaric acid derivatives such as (-) - O, O'-dipivaloyl-L-tartaric acid or (-) - O, O'-diacetyl-L-tartaric acid no salt formation could be observed.

In further processing of the subject, it has surprisingly been found that aromatic or heteroaromatic substituted derivatives of tartaric acid are excellently suited to form "diastereomer salts" from the racemate (II).

in (Ia) und/oder (I)

mit chiralen substituierten Weinsäureestern der allgemeinen Formeln (IIIa) oder (IIIb)

wobei Ar für einen unsubstituierten oder substituierten Aromaten oder Heteroaromaten steht.The subject matter of the present application is therefore the racemate resolution of (II)

in (Ia) and / or (I)

with chiral substituted tartaric acid esters of the general formulas (IIIa) or (IIIb)

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic.

durch Racematspaltung von (II)

mit einem chiralen substituierten Weinsäureester der Formel (IIIa)

wobei Ar für einen unsubstituierten oder substituierten Aromaten oder Heteroaromaten steht.A further subject matter relates to processes for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxy amide of the formula (I)

by racemate resolution of (II)

with a chiral substituted tartaric acid ester of the formula (IIIa)

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic.

The term "substituted" means that one or more hydrogen atoms on the atom or group in question have been replaced by a choice from the group indicated, provided that the normal valency of the atom in question has not been exceeded under the present circumstances becomes. Combinations of substituents and / or variables are permissible.

The term "unsubstituted" means that no hydrogen atom has been replaced.

The heteroaryl group may be a 5-membered heteroaryl group such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group such as pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group such as carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzothiazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, indolizinyl or purinyl; or a 10-membered heteroaryl group such as quinolinyl, quinazolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinoxalinyl or pteridinyl.

In particular, the heteroaryl group is a pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl or pyrimidinyl group.

Aryl group within the meaning of the present application is in particular a phenyl group.

Suitable substituents for the purposes of the present invention are halogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, nitrile, a nitro group, cyano group, CF 3 group or amide group, for example NHCOR, in the R for methyl, Ethyl or phenyl, or a -NRCOR group in which R has the abovementioned meaning, or a CONHR in which R has the abovementioned meaning, or a CONRR 'in which R' is identical to R as defined above or cyclic amides such as - COMorpholin residue, -COPiperidin residue

The term halogen denotes a fluorine, chlorine, bromine or iodine atom, in particular a fluorine, chlorine or bromine atom.

The term "C ₁ -C ₆ alkyl" means a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, e.g. As a methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, tert- butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl , 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl , 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl group or an isomer thereof. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C ₁ -C ₄ -alkyl"), eg. Example , a methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl or tert-butyl group, in particular 1, 2 or 3 carbon atoms ("C ₁ -C ₃ alkyl"), z , As a methyl, ethyl, n- propyl or isopropyl group.

The term "C ₁ -C ₆ -alkoxy" means a straight-chain or branched saturated monovalent group of the formula (C ₁ -C ₆ -alkyl) -O-, in which the term "C ₁ -C ₆ -alkyl" as defined above is, for. Example, a methoxy, ethoxy, n- propoxy, isopropoxy, n- butoxy, sec- butoxy, isobutoxy, tert- butoxy, pentyloxy, isopentyloxy or n- Hexyloxygruppe or an isomer thereof.

Preferably Ar stands for:

Wherein R1, R2, R3, R4, R5 each represents a hydrogen atom or an alkyl group such as methyl, ethyl, propyl or a halogen atom such as fluorine, chlorine, bromine or iodine or an ether group such as O-methyl , O-ethyl, O-phenyl, or a nitro group, cyano group, CF3 group or amide group, such as NHCOR, in which R may be methyl, ethyl or phenyl, or an -NRCOR group in the R above Has meaning or a CONHR in which R has the abovementioned meaning, or a CONRR 'in which R' is identical to R as defined above or cyclic amides such as -COMorpholin radical, -COPiperidin rest. The substitution patterns can be very different, so theoretically up to 5 different substituents may be possible, but usually the monosubstituted Ar radicals are preferred. But Ar can also be a substituted heteroaromatic, as preferably. Pyridine or pyrazine. It may be also a political aromatic hydrocarbon, such as. for example, a substituted naphthalene, anthracene, or quinoline act.

worin * für die Verknüpfungsstelle steht.Particularly preferred as Ar are:

where * represents the point of attachment.

worin * für die Verknüpfungsstelle steht.Most preferably, Ar stands for:

where * represents the point of attachment.

worin * für die Verknüpfungsstelle steht.Very particularly preferred Ar radicals are:

where * represents the point of attachment.

Of which the unsubstituted ring (phenyl) is particularly preferred.

The preparation of tartaric acid esters is known from the literature, such as in Organic Synthesis, Coll. Vol. 9, p.722 (1998 ); Vol. 72, p.86 (1995 ), as in Chirality 2011 (23), 3, p.228 described.

oder

worin Ar für einen unsubstituierten oder substituierten Aromaten oder Heteroaromaten steht und die oben angegebene Bedeutung hat.Another object also relates to diastereomer salts according to the formulas

or

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic and has the meaning given above.

Particularly preferred are diastereomer salts in which Ar is phenyl.

worin Ar für einen substituierten oder unsubstituierten Aromaten oder Heteroaromaten steht.Whether this is really a classical diastereomeric salt or a 1: 1 molecule complex stabilized by hydrogen bonding is not clearly predictable. However, it is clear that these 1: 1 molecular aggregates are very stable and can behave and isolate like classic diastereomeric salts, so that we will use the name diastereomeric salt in the following. For the preparation of the diastereomer salts, tartaric acid derivatives of the general formula (IIIa) and (IIIb) are used:

wherein Ar is a substituted or unsubstituted aromatic or heteroaromatic.

The preparation of the diastereomeric salts is carried out as follows:

The reaction of the racemic mixture (II) with a tartaric acid derivative of the general formula (IIIa) or (IIIb) gives the 4 possibilities of diastereomeric salt formation (IV a-d). Surprisingly, a certain preference is observed in that, for example, when reacting rac- (II) with a tartaric acid derivative of general formula (IIIa), in most cases the diastereomeric salt of general formula (IVa) is obtained Antipode of the S configuration prefers the formation of salt. The diastereomer salt (IVa) precipitates almost quantitatively from the solution, from which it is subsequently added, e.g. can be isolated by filtration with the antipode remaining in solution with the R configuration. In much the same way, the mirror-image salt of the general formula (IVb) is prepared by reacting the racemate (II) with the tartaric acid derivative of the general formula (IIIb), the antipode of the R configuration preferably undergoing salt formation. The precipitated diastereomeric salts can be separated almost quantitatively, in which case the S-antipode remains in solution.

The stoichiometric ratio of (II) to (IIIa) or (IIIb) as well as the choice of solvent can be used to optimize the yield and the enantiomeric purity.

Since finerenone (I) has the S configuration, the S, S-configured tartaric acid derivatives are preferably used for racemate resolution, since in this case the diastereomeric salt of the S antipode is preferably formed.

It will be 0.4 to 1.2 eq. Tartaric acid ester (IIIa) or (IIIb) used for the racemate resolution, but preferably from 0.4 to 0.7 eq. however, more preferably 0.45 to 0.6 eq, but most preferably 0.50 -0.55 eq.

Diastereomeric salt formation occurs in solvent mixtures consisting of water and water-miscible organic solvents.

Suitable organic solvents for the purposes of the application are, for example, ethanol, methanol, isopropanol, 1-propanol, ethyl acetate, isobutanol, dichloromethane, 1-pentanol or acetone, but ethanol is preferably used. The solvents may also be in the commercial denatured form, such as the denaturant used in the ethanol, e.g. Toluene, methyl ethyl ketone, thiophene, hexane are used, which for cost reasons, brings great benefits, therefore, is particularly suitable for large-scale use of spirits which in the meaning of the application from ethanol which may be denatured with toluene or methyl ethyl ketone. For the purposes of the present application, therefore, ethanol is to be understood below as the solvent in addition to pure ethanol and, in particular for large-scale use, brandy in the sense of the abovementioned definition. In addition, the following solvents were also used: ethyl acetate / methanol 90:10; Methanol / water 80:20; Ethanol / water 90:10; Ethanol / water 85:15; Ethanol / water 80:20; Ethanol / water 75:25; Ethanol / water 70:30; dichloromethane; 1-propanol / water 80:20; 1-pentanol; 1-pentanol / water 90:10; isopropanol; Isopropanol / water 80:20; Isobutanol / water 90:10; Isobutanol / water 80:20; Cyclohexanol / water 90:10; Benzyl alcohol / water 90:10; ethylene glycol; Ethylene glycol / water 80:20.

Preferably, the racemate resolution is carried out in ethanol / water mixture, wherein mixtures (vol / vol) in the range of ethanol: water = 1: 1 to 6: 1. Preferably, however, a mixture of ethanol: water = 4: 1 to 3: 1 is used. Particularly preferably, a mixture of ethanol: water = 3: 1 is used. The mixture can be prepared beforehand, or in situ, after all components have been produced in a pot. The solvent mixture can be used in 10 to 40-fold excess, based on the racemate (II), e.g. on 1kg racemate 10L to 40L solvent mixture are used. Preference is given to a 10 to 20-fold excess, in particular 13 to 16-fold excess - particularly preferred is a 14 to 15-fold excess.

Usually, the racemate resolution is carried out by initially introducing all components in the solvent mixture at room temperature, then heated to 60 to 80 ° C, but preferably to 75 ° C and 2 to 10 hours, preferably stirred for 3 to 4 hours at 75 ° C and then within from 3 to 10 hours, preferably 4 to 5 hours to room temperature (about 20 to 23 ° C) cools (by means of a temperature ramp). Then allowed to stir for 2 to 24 hours, preferably 5 to 18 hours, most preferably 12 to 16 hours at room temperature. The racemate resolution is preferably carried out at a temperature of 75 ° C

Subsequently, the precipitated diastereomer salt (IVa), (IVb), (IVc) and / or (IVd) are isolated.

The isolation is carried out by methods known to those skilled in the art, for example by filtration or via a centrifuge. The filter cake thus obtained can be washed once or several times with a solvent or solvent mixture. Subsequently, a Drying under vacuum, preferably <100 mbar at elevated temperature (50 to 80 ° C, preferably 50 ° C). The use of towing gas has proven to be advantageous in some cases.

With the procedure described above, it is possible to prepare chemically very pure diastereomeric salts. The enantiomeric excess of the diastereomeric salts is usually> 97% e.e. (see examples)

The diastereomer salts do not necessarily have to be dried, but can also be used moist in the next process stage.

The process steps can also be combined or exchanged in the order in addition to the usual procedure mentioned above, as shown in the following Table 2: <b> Table 2 </ b> Step 1 2nd step 3rd step 4th step 5th step Preparation of racemate (II) and diaryl-tartaric acid (IIIa or b) Adding ethanol Adding water Heat Submission of racemate (II) Adding ethanol Addition of diaryl-tartaric acid (IIIa or b) Adding water Heat Submission of racemate (II) Adding water Addition of diaryl-tartaric acid (IIIa or b) Adding ethanol Heat Preparation of diaryl-tartaric acid (IIIa or b) Adding ethanol Addition of racemate (II) Adding water Heat Preparation of diaryl-tartaric acid (IIIa or b) Adding water Addition of racemate (II) Adding ethanol Heat Preparation of racemate (II) and diaryl-tartaric acid (IIIa or b) Add the ethanol-water mixture Heat Submission of racemate (II) Add the ethanol-water mixture Addition of diaryl-tartaric acid (IIIa or b) Adding ethanol Heat Preparation of diaryl-tartaric acid (IIIa or b) Add the ethanol-water mixture Addition of racemate (II) Adding water Heat Submit ethanol-water mixture Addition of racemate (II) Addition of diaryl-tartaric acid (IIIa or b) Heat Submit ethanol-water mixture Addition of diaryl-tartaric acid (IIIa or b) Addition of racemate (II) Heat Presentation of ethanol Addition of racemate (II) Adding water Addition of diaryl-tartaric acid (IIIa or b) Heat Presentation of water Addition of racemate (II) Adding ethanol Addition of diaryl-tartaric acid (IIIa or b) Heat Presentation of ethanol Addition of diaryl-tartaric acid (IIIa or b) Adding water Addition of racemate (II) Heat Presentation of water Addition of diaryl-tartaric acid (IIIa or b) Adding ethanol Addition of racemate (II) Heat

Depending on the plant type in the pilot plant or in production, one or the other variant may be advantageous.

In the next step, the diastereomer salt is treated with a base and the solvent removed. The removal of the solvent is carried out by methods known to those skilled in the art, for example by distilling off. To prepare the chiral compounds (I) and (Ia), the diastereomeric salt of the general formula (IVa), (IVb), (IVc) or (IVd) must be treated with a base, the target molecule (I) or ( Ia) after distilling off the organic solvent from the solution, is isolated - for example, by filtration and washed and the respective tartaric acid ester of formula (IIIa) or (IIIb) remains in salified form in solution.

Suitable bases for the purposes of the present invention are inorganic and organic bases. In the case of inorganic bases, ammonia, caustic soda, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate can be used. However, sodium hydroxide, sodium phosphate or potassium phosphate is preferably used. Particular preference is given to using sodium phosphate or potassium phosphate. It is important to emphasize that the inorganic bases can be used both in anhydrous form and in the form of their hydrates, eg sodium phosphate (anhydrous) and sodium phosphate hydrate can be successfully used. As the organic base, aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hünig base, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) can be used.

The release of the target compound (I) or (Ia) takes place in mixtures of water, with water-miscible organic solvents, such as ethanol, isopropanol, 1,2-ethanediol, methoxyethanol, methanol or acetone, but preferably ethanol is used. The solvents may also be in the commercial denatured form, such as the denaturant used in the ethanol, e.g. Toluene, methyl ethyl ketone, thiophene, hexane are used, preferably brandy which in the meaning of the application of ethanol which may be denatured if necessary with toluene or methyl ethyl ketone is used, which brings great advantages for cost reasons. It has proved advantageous to use mixtures of water and ethanol, with mixtures (vol / vol) being in the range of ethanol: water = 1: 6 to 1: 3. Preferably, however, a mixture of ethanol: water = 1: 4 is used. The mixture can be prepared beforehand, or in situ, after all components have been produced in a pot. It is possible to use 7 to 20 times of this mixture, based on the diastereomer salt used (IVa or IVb or IVc or IVd), e.g. 1 kg in 7 L to 20 L of this mixture. Preference is given to using 8-12 times this mixture, more preferably 9-11 times this mixture is used, most preferably 10 times.

The release of the target compound (I) or (Ia) is carried out by initially introducing the diastereomer salt (IVa or IVb or IV c or IVd) in a solvent mixture at 0 to 80 ° C, preferably 20 to 50 ° C, then by adding the organic or inorganic base (either in solid form, or as a solution, preferably in water), a pH of 6.9 to 9.5, preferably a pH of 7.0 to 8.0, more preferably pH 7.5 sets , The base may optionally be added very fast (within a few minutes) or very slowly (within several hours), such as in 5 minutes to 3 hours. A faster addition is preferred in any case, is preferred within 5 min. dosed up to 1 hour. For this purpose, a built-in reactor pH meter can be used with which to control the setting and slowly dosed the base. However, it is also possible from the outset to add a fixed amount of base (solid or dissolved in a solvent) which, on the basis of experience, ensures that the desired pH range is preferably reached. Such a procedure is particularly preferred in production. It has proved to be advantageous if, after the pH has been adjusted, stirring is continued at from 10 to 80 ° C., preferably from 20 to 60 ° C., preferably from 40 to 60 ° C. The stirring time may be 1 to 10 hours, preferably 2-5 hours, more preferably 3-4 hours. It is then allowed to cool to 15-25 ° C, e.g. over a ramp and can then stir again for 1 to 64 hours (the 64 hours are used to demonstrate the robustness of the process, see Example 3b), but is preferably stirred for 3 to 24 hours, but generally sufficient 10 to 20 hours.

The isolation is carried out by methods known to those skilled in the art, for example by filtration or via a centrifuge. The filter cake thus obtained can be washed once, or several times with a solvent or solvent mixture. Subsequently, a Drying under vacuum, preferably <100 mbar at elevated temperature (50 to 80 ° C, preferably 50 ° C). The use of towing gas has proven to be advantageous in some cases.

However, it is also possible to dissolve the material obtained in ethanol or mixtures of water with ethanol from the filter and then to go after adjustment of the amount of water / ethanol in the eluate immediately in the next step (see below). This procedure is particularly preferred on an industrial scale, since this can save a drying step.

With the procedure described above, it is possible to produce chemically very pure crude products. The enantiomeric excess of the crude products (I) and (Ia) is generally> 96.5% e.e.

In the context of up-scaling, it has been shown that the more complete separation of the tartaric acid esters (IIIa) and (IIIb) from the crude products (I) and (Ia) is technically not always very easy to carry out and the contents of these components are closely related to Limit of specification moves. Since the requirements for the specification in the final active ingredient are very high (<0.1% (III a) in the final active substance), it has proved advantageous in some cases to join a further process step which ensures that the content of tartaric acid ester ( IIIa) is reduced to less than 0.15%, preferably less than 0.1% and in particular less than 0.05%, and the final active substance is reproducibly obtained in accordance with the specification. The tartaric acid ester (IIIa), is hardly, or almost never depleted in the final crystallization to pure product, so that such a downstream process step guarantees that a robust way of driving the overall process is ensured, also works with almost loss. This method step, which ensures that compound (IIIa) is depleted to below 0.15%, preferably below 0.1% and in particular below 0.05% in the active ingredient, is likewise the subject matter of the present invention. The method of reducing (IIIa) is carried out as follows. For this purpose, the dried or advantageously the still moist crude product of (I) or (Ia) is used. For this purpose, a base is again used: For the removal of tartaric acid esters of the formula (III) a or (IIIb) inorganic and organic bases can be used. In the case of inorganic bases, ammonia, caustic soda, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate can be used. However, sodium hydroxide, sodium phosphate or potassium phosphate is preferably used. Particular preference is given to using sodium phosphate or potassium phosphate. It is important to emphasize that the inorganic bases can be used both in anhydrous form and in the form of their hydrates, eg sodium phosphate (anhydrous) and sodium phosphate hydrate can be successfully used. As the organic base, aliphatic or aromatic bases such as triethylamine, imidazole, N-methylimidazole, Hünig base, pyridine, DBU can be used.

The depletion of (IIIa) or (IIIb) is carried out in mixtures of water, with water-miscible organic solvents, such as ethanol or isopropanol, 1,2-ethanediol, methoxyethanol or methanol, or isopropanol or acetone, but preferably ethanol is used , The solvents may also be in the commercial denatured form, such as the denaturant used in the ethanol, e.g. Toluene, methyl ethyl ketone, thiophene, hexane are used, which brings great advantages for cost reasons. It has proven to be advantageous to use mixtures of water and ethanol, with mixtures (vol / vol) in the range of ethanol: water = 30: 10 to 10: 10. Preferably, however, a mixture of ethanol: water = 20: 10 is used. The mixture can be prepared beforehand, or in situ, after all components have been produced in a pot. The solvent mixture can be used in 10 to 20 times the excess, based on the diastereomer salt used (Iva), IVb, IVc or IVd, ie. 1 kg in 10 L to 20 L of this mixture. Preferably 10 to 14 times this mixture is used, more preferably 11-12 times this mixture is used.

The depletion of (IIIa) or (IIIb) is carried out by initially charging at 40 to 80 ° C., preferably 50 to 70 ° C., in a solvent mixture, as described above, then adding the organic or inorganic base (either in solid form, or as a solution, preferably, water), a pH of 6.9 to 9.5, preferably a pH of 7.5 to 9.0, more preferably adjusted to pH 8.5. The base may optionally be added very fast (within a few minutes) or very slowly (within several hours), for example in 1 minute to 3 hours. A faster addition is preferred in any case, is preferred within 1 min. dosed up to 1 hour. For this purpose, a built-in reactor pH meter can be used with which to control the setting and slowly dosed the base. However, it is also possible from the outset to add a fixed amount of base (solid or dissolved in a solvent) which, on the basis of experience, ensures that the desired pH range is preferably reached. Such a procedure is most preferred in production. It has proved to be advantageous if, after the pH has been adjusted, stirring is continued at 40-80 ° C., preferably 50-75 ° C., preferably 60-70 ° C. The stirring time may be 1 to 24 hours, preferably 2-10 hours, more preferably 2-4 hours. Subsequently, the organic solvent is largely distilled off, this can be done at atmospheric pressure or gentler under reduced pressure. As soon as the organic solvent has distilled off, it is allowed to cool to 15-25 ° C, e.g. via a ramp and can then be stirred again for 1 to 64 hours (the 64 hours are used to demonstrate the robustness of the process, see Example 3b), but preferably is stirred for 1 to 24 hours, but usually 1-5 hours are sufficient.

The isolation is carried out by methods known to those skilled in the art, for example by filtration or via a centrifuge. The filter cake thus obtained can be used once or several times with a Solvent, or solvent mixture washed. This is followed by drying under reduced pressure, preferably <100 mbar at elevated temperature (50 to 80 ° C, preferably 50 ° C). The use of towing gas has proven to be advantageous in some cases.

It is also possible before distilling off the solvent, the pH with an organic acid, such as formic acid, citric acid, acetic acid or inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid or an acidic salt, such as sodium dihydrogen phosphate, potassium bisulfate or sodium bisulfate to pH 5 - 7 and then proceed as described above.

With the procedure described above, it is possible to produce chemically very pure crude products. The enantiomeric excess of the crude products (I) and (Ia) is generally> 97% ee, the content of (IIIa) or (IIIb) is below 0.15%, preferably below 0.1% and in particular below 0, 05% reduced.

It has proved to be advantageous to subject such a crude product of the formula (I) or (Ia) nor a subsequent crystallization to improve both the chemical and especially the optical purity, since the enantiomeric excesses of the crude products usually> 97% ee lie. For this purpose, a final crystallization process was developed: For this purpose, the crude product (I) or (Ia) is dissolved in ethanol, (optionally by heating) and then subjected to particle filtration, preferably spirits or toluene-denatured ethanol is used for GMP technical reasons. In some cases, depending on the technical equipment, the crystallization can also under pressure, at elevated temperature drive (advantage: less solvent), but it can also be recrystallized from aqueous ethanol solutions (under pressure or at atmospheric pressure). Then it is concentrated under normal pressure or under reduced pressure to about 3 to 6 times the volume, preferably 4 to 5 times, while the product crystallizes out. In some cases, if e.g. large volumes must be distilled off over long periods, it has proven advantageous to distill off under reduced pressure, keeping the internal temperature low to avoid decomposition and by-product formation. After completion of the distillation is cooled to 0 ° C and then the crystals are isolated and dried in vacuo at 40 to 50 ° C. The yields are usually> 88% d. Theory. The achieved chemical, purity and content correspond to the criteria for commercial products according to ICH Guideline. Residual solvent, in this case ethanol, is usually <0.05% in the pilot plant. The optical purity is »99% e.e.

As a particularly preferred method, in particular for the large-scale implementation, one uses (+) - dibenzoyl-tartaric acid (V), it can be used both the anhydrous form, as well as the hydrate:

erfolgt bevorzugt in einem Branntwein-Wasser-Gemisch unter Verwendung von Natriumphosphat als Base. In Fällen, in denen eine Umarbeitung nötig ist, wenn der Anteil an (+)-Dibenzoyl-Weinsäure (V) > 0,15 % beträgt

erfolgt die Umarbeitung bevorzugt in einem Branntwein-Wasser-Gemisch unter Verwendung von Natriumphosphat als Base. Die finale Kristallisation zu Finerenone, rein erfolgt bevorzugt in Branntwein als Lösungsmittel. Dabei wird eine Reinheit von 0,15% bevorzugt 0,1% besonders bevorzugt unter 0,05% erreicht.The racemate resolution is preferably carried out in a spirits-water mixture. The subsequent release of finerenone, crude

is preferably carried out in a brandy-water mixture using sodium phosphate as the base. In cases where conversion is necessary when the proportion of (+) - dibenzoyl-tartaric acid (V)> 0.15%

the conversion is preferably carried out in a spirits-water mixture using sodium phosphate as the base. The final crystallization to Finerenone, pure is preferably carried out in spirits as a solvent. In this case, a purity of 0.15%, preferably 0.1%, particularly preferably less than 0.05%, is achieved.

It is also possible to isolate the target enantiomer from the mother liquor. Here, first, the corresponding diastereomeric salt (IVa), (IVb), (IVc) or (IVd) is prepared from either (I) or (Ia), then isolated by filtration and then the mother liquor, which then contains the respective antipodes by Addition of a base, such as ammonia, sodium hydroxide, lithium hydroxide, potassium hydroxide, ammonium carbonate, sodium carbonate, potassium carbonate, lithium carbonate, ammonium bicarbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium phosphate, preferably sodium hydroxide, sodium phosphate and potassium phosphate, more preferably sodium phosphate and potassium phosphate, the pH adjusted to pH> 7, preferably pH is 7.5. Subsequently, the organic solvent, preferably ethanol is distilled off, either at atmospheric pressure or gentler under reduced pressure, thereby precipitating the corresponding antipode. The product is filtered off, washed with water or water / solvent mixtures and dried. A corresponding final crystallization from spirits, as described for example in Example 1c provides the compounds (I) and (Ia) in a correspondingly pure form.

mit Dibenzoylweinsäure der Formel (V)

in einem Branntwein/ Wasser Gemisch zu dem Diastereomerensalz (VI)

umsetzt und anschließend Finerenone (I)

unter Einsatz von Natriumphosphat ebenfalls in einem Branntwein/ Wasser Gemisch freisetzt und anschliessend erneut mit Natriumphosphat in Branntwein/ Wassergemisch umsetzt und dann reines Finerenone mit einem Dibenzoylweinsäuregehalt ≤ 0,15% auskristallisiert; in einer besonders bevorzugten Ausführungsform erhält man Finerenone mit einem Dibenzoylweinsäuregehalt ≤ 0,1%, insbesondere bevorzugt unter 0,05% Dibenzoylweinsäuregehalt.A further subject of the present application is therefore finerenone (I) having a dibenzoyltartaric acid content ≤ 0.15% obtained by reacting the racemate (II)

with dibenzoyltartaric acid of the formula (V)

in a spirits / water mixture to the diastereomer salt (VI)

and then Finerenone (I)

using sodium phosphate also released in a spirits / water mixture and then reacted again with sodium phosphate in spirits / water mixture and then crystallized pure finerenone with a dibenzoyltartaric acid content ≤ 0.15%; In a particularly preferred embodiment, finerenones having a dibenzoyltartaric acid content ≤ 0.1%, particularly preferably less than 0.05% dibenzoyltartaric acid content are obtained.

Experimental part Abbreviations and acronyms:

EtOH

ethanol

DB tartaric acid

dibenzoyltartaric

DMSO

dimethyl sulfoxide

d.Th

Theory (at yield)

HPLC

High pressure, high performance liquid chromatography

1H-NMR

1H nuclear magnetic resonance spectrometry

IT

internal temperature

MS

Mass spectrometry

RT

Retention Time

RRT

Relative retention time

TFA

trifluoroacetic

TM

jacket temperature

XRPD

X-ray powder diffraction (powder diffractometer)

spirits

Ethanol denatured with 2% toluene

Examples

Verunreinigung A

Verunreinigung B

Verunreinigung C (unbekannte Struktur, immer signifikant unter 0,1 %) Verunreinigung D

Verunreinigung E

Verunreinigung F

Verunreinigung G

Verunreinigung H

Verunreinigung I

Verunreinigung J

Verunreinigung K

Verunreinigung N (III)

Table 3 below shows the structures of the compounds found in HPLC again. The assignment of the retention times in the HPLC is given below. <b> Table 3 </ b> Finerenone (I)

Pollution A

Contamination B

Pollution C (unknown structure, always significantly below 0.1%) Contamination D

Pollution E

Pollution F

Pollution G

Contamination H

Pollution I

Pollution J

Impurity K

Pollution N (III)

1) Analytical method for checking the content of impurities and enantiomeric purity at the stage of di-benzoyltartaric acid

salary and organic impurities RT (min) RRT Di-benzoyl-tartaric acid Approximately 11.1 1.00

Mono-benzoyltartaric acid Approximately 5.1 0.46

benzoic acid Approximately 7.6 0.69

Device: Ultra-high performance liquid chromatograph (with a pressure range up to 1200 bar with thermostated column oven, and UV detector Pillar : YMC Triart C8 Length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 μm Max pressure: 1000 bar Conditions: 20 ° C; 0.50 mL / min; 1,7μL (10 ° C); 240nm / 6 nm eluent: A: 0.1% TFA in water; B: acetonitrile Gradient: Time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 enantiomeric purity: RT (min) RRT (+) - di-benzoyl-tartaric acid 2.1 1.00 (-) - di-benzoyl-tartaric acid 3.9 1.86 Device: High performance liquid chromatograph with thermostated column oven and UV detector Pillar : Chiralpak IC Length: 250 mm, inner diameter: 4.6 mm, grain size: 5.0 μm Max pressure: 300 bar Conditions: 40 ° C; 2.0 mL / min; 5 μL; 234nm / 6 nm eluent: A: heptane; B: 0.1% TFA in ethanol isocratic: A (%) 80: B (%) 20

2) Analytical method for checking the content of impurities and enantiomeric purity at the stage of the diastereomer salt

Content and organic impurities RT (min) RRT Finerenone (I) 6.2 1.00 Pollution A 3.3 0.53 Contamination B 3.7 0.60 VerunreinigungC 3.9 0.62 Contamination D 4.4 0.70 Pollution E 5.5 0.89 Pollution F 6.8 1.10 Pollution G 7.2 1.17 Contamination H 7.7 1.25 Pollution I 7.8 1.27 Pollution J 8.4 1.36 Impurity K 10.4 1.69 Pollution N 11.1 1.80 Device: Ultra-high performance liquid chromatograph (with a pressure range up to 1200 bar with thermostated column oven, and UV detector Pillar : YMC Triart C8 Length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 μm Max pressure: 1000 bar Conditions: 20 ° C; 0.50 mL / min; 3,5μL (10 ° C); 242 nm / 6nm eluent: A: 0.1% TFA in water; B: acetonitrile Gradient: Time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 enantiomeric purity: RT (min) RRT Finerenone (I) 5.34 1.00 (Ia) 6.14 1.15 Device: High performance liquid chromatograph with thermostated column oven and UV detector Pillar : Lux 3μm i-cellulose-5 Length: 150 mm, inner diameter: 4.6 mm, grain size: 3.0 μm Max pressure: 300 bar Conditions: 40 ° C; 1.0 mL / min; 10 μL (20 ° C); 252nm / 6 nm eluent: A: 20 mmol ammonium acetate buffer pH 9.0 (1.54 g ammonium acetate in 1 L Milli-Q water and adjusted to pH 9.0 with ammonia); B: acetonitrile isocratic: A (%) 50: B (%) 50

3) Analytical method for testing the content of impurities and enantiomeric purity at the level Finerenone, crude (I).

Content and organic impurities RT (min) RRT Finerenone (I) 6.2 1.00 Pollution A 3.3 0.53 Contamination B 3.7 0.60 Pollution C 3.9 0.62 Contamination D 4.4 0.70 Pollution E 5.5 0.89 Pollution F 5.6 0.91 Pollution G 6.8 1.10 Contamination H 7.6 1.23 Impurity K 10.4 1.68 Pollution N 11.1 1.79 Device: Ultra high performance liquid chromatograph (with a pressure range up to 1200 bar with thermostated column oven and UV detector Pillar : YMC Triart C8 Length: 100 mm, inner diameter: 3.0 mm, grain size: 1.9 μm Max. Pressure: 1000 bar Conditions: 20 ° C; 0.50 mL / min; 1,7μL (10 ° C); 252 nm / 6nm and 230nm / 6nm for the evaluation of DB-tartaric acid eluent: A: 0.1% TFA in water; B: acetonitrile Gradient: Time (min) A (%) B (%) 0.0 90.0 10.0 15.0 35.0 65.0 16.0 20.0 80.0 20.0 20.0 80.0 enantiomeric purity: RT (min) RRT Method A Finerenone (I) Approximately 11 1.00 (Ia) Approximately 9 0.82 Device: High performance liquid chromatograph with thermostated column oven and UV detector Pillar : Chiralpak IA Length: 250 mm, Inner diameter: 4.6 mm, Grain size: 5.0 μm Max. Pressure: 300 bar Conditions: 40 ° C; 0.8 mL / min; 5 μL (20 ° C); 255 nm / 6 nm eluent: A: acetonitrile; B: methyl tert-butyl ether (MTBE) isocratic: A (%) 90: B (%) 10 enantiomeric purity: RT (min) RRT Method B Finerenone (I) 5.7 1.00 Enantiomer (Ia) 6.8 1.19 Device / detector: High performance liquid chromatograph with thermostated column oven, UV detector and data evaluation system Measurement wavelength: 252 nm Oven temperature: 40 ° C Pillar: Chiralpak IC Length: 150 mm, inner diameter: 4.6 mm, grain size: 3 μm Mobile phase: A: 50% buffer 20mM ammonium acetate pH 9 B: 50% acetonitrile River: 1 mL / min Running time: 8 min equilibration: not necessary, isocratic Sample solvent: superplasticizer Test solution: approx. 0.5 mg / ml of the substance racemate, dissolve with sample solvent Reference solution: A comparative solution is prepared analogously to the test solution Inj ect volume: 10 μL

The enantiomeric determination measurements given in the following examples were all determined by method B. Some values, above all the batches produced in the pilot plant, were compared with method A for comparison and gave comparable results.

The HPLC analysis data given in the following examples with regard to purity and content for the end product Finerenone, pure (I) relate only to impurities which are present in the product as> 0.05%. This is essentially Contaminant E. All other contaminants shown in the table above are typically <0.05%. The structure of such impurities was determined by isolation from enriched mother liquors.

example 1

Laboratory Approach Using Anhydrous (+) - O, O-Dibenzoyl-D-tartaric Acid (III)

Example 1a Tartrate salt (IV) preparation

250 g (660.616 mmol) of finerenone (II) racemate were initially charged in 3500 ml of a mixture consisting of ethanol, toluene denatured / water = 75:25 (v / v) at room temperature (about 23 ° C.). 130.2 g (363.339 mmol) of (+) - O, O-dibenzoyl-D-tartaric acid (III) were added via a solids funnel and then with 250 ml of a mixture consisting of ethanol, toluene denatured / water = 75:25 ( v / v) rinsed. The suspension thus obtained was heated within 0.75 hours to 75 ° C internal temperature and then stirred for 3.0 hours at this temperature. It was then cooled over a cooling ramp from 23 ° C within 5.0 hours and stirred overnight (about 16 hours) at this temperature. The suspension was filtered through a frit and washed once with 250 ml of a mixture consisting of ethanol, toluene denatured / water = 75:25 (v / v). Moisture yield: 334.7 g. The wet product was then left overnight (about 16 hours) at 50 ° C dried under vacuum (<100 mbar). Yield: 250.2 g (100.08% of theory) of a colorless crystalline powder

Analytical results:

Finerenone (I) 47.2% by weight (HPLC) enantiomeric excess 97.68% e.e. Largest unknown minor component at RT 5.606 min. 0.47% Residual solvents: EtOH 2.24% toluene 0.0%

• MS (EIpos): m / z = 379 [M + H] ⁺
• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.39 (s, 1H), 5.89 (s, 2H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H), 7.61 (t, 4H), 7.69 (s, 1H), 7.75 (t, 2H), 8.04 (d, 4H), 12.50-15, 40 (very broad signal, 2H) and signal from the solvent DMSO and increased water signal: δ = 2.5-2.6, as well as small peaks at δ = 3.40 - 3.50 (q) and δ = 1, 05-1.10 (t), superimposed signals from residual solvent ethanol.

Example 1b Preparation of crude product (I)

248 g of the compound (IV) prepared in Example 1a were suspended at room temperature in 2480 ml of a mixture consisting of ethanol, toluene denatured / water = 20:80 (v / v) (a pH of pH = 4 was measured). , Subsequently, 819.6 g of an aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) were added dropwise within 60 minutes and the pH adjusted to pH = 7.2. The mixture was stirred for a further 50 minutes at 23 ° C. (pH = 7.1). Subsequently, 98.3 g of an aqueous sodium phosphate solution (100 g of sodium phosphate dissolved in 1000 ml of water) were added dropwise within 10 minutes and the pH adjusted to pH = 7.5. It was heated to 50 ° C inside temperature within one hour and stirred at this temperature for 3.0 hours. It was cooled within one hour to 22 ° C and stirred for one hour at this temperature. The crystals are filtered through a frit and washed once with 200 ml and once with 100 ml of a mixture consisting of ethanol, toluene denatured / water = 20:80 (v / v) and washed twice with 200 g of water. Wet yield: 263.4 g. The moist product was then übers Weekend (> 48 hours) at 50 ° C under vacuum (<100 mbar) dried. Yield: 116.9 g (93.52% of theory) of a colorless crystalline powder.

Analytical results:

Finerenone (I) Purity: 99.86% area (HPLC); Content: 100.0% by weight enantiomeric excess 97.02% e.e. Largest minor component contamination E 0.07% Residual solvents: EtOH 0.19% toluene 0.13% Water (Karl Fischer) 0.042%

• MS (EIpos): m / z = 379 [M + H] ⁺
• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H) , 7.69 (s, 1H) and signal from solvent DMSO and significantly increased water signal: δ = 2.5-2.6, and a very small peak at δ = 3.38 (not assigned)

Example 1c Production of pure product (I)

116.0 g of the crude product (I) prepared in Example 1b were suspended in 2330 ml of ethanol, toluene denatured and then heated to reflux. The product went into solution. It was stirred for an hour at this temperature. The solution was filtered through a heated pressure filter (T = 75 ° C), the pressure filter then rinsed with 30 ml of ethanol, toluene denatured. The solvent was subsequently distilled off (about 1920 ml were distilled off) until a final volume of about 4 times (based on the substance used: 116 g × 4 ~ 484 ml) was reached. It was then cooled to 23 ° C internal temperature (duration about 1.5 to 2 hours). Then it was stirred for 2 hours at 3 ° C internal temperature. The product was filtered off and washed once with 100 ml of ethanol, toluene denatured. Moisture yield: 124 g. The moist product was dried at 50 ° C over the weekend (> 48 h) under vacuum (<100 mbar). Yield: 112.6 g (97.07% of theory) of a colorless crystalline powder, fine needle crystals.

Analytical results:

Finerenone (I) Purity: 99.86 area (HPLC); Content: 99.5% by weight enantiomeric excess 100% e.e. Largest minor component contamination E 0.07% Residual solvents: EtOH 0.05% toluene 0.00% Water (Karl Fischer) 0.00%

• MS (EIpos): m / z = 379 [M + H] ⁺
• ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 1.05 (t, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 3.99-4.07 (m, 2H), 5.37 (s, 1H), 6.60-6.84 (m (broad signal), 2H), 7.14 (d, 1H), 7.28 (dd, 1H), 7.37 (d, 1H), 7.55 (s, 1H) , 7.69 (s, 1H) and small signals of solvent DMSO and water at δ = 2.5-2.6 and a very small peak at δ = 3.38 (not assigned)
• Modification: Mod A (as defined in WO2016 / 016287 A1 )

Example 2

Laboratory approach using (+) - O, O-dibenzoyl-D-tartaric acid hydrate (III)

Example 2a Tartrate preparation

350.0 g of racemate (II) were initially charged at room temperature and then added to 3112 g of spirits. Then, 1200 g of water was added. 191.4 g% (+) - O, O-dibenzoyl-D-tartaric acid monohydrate (III) were added via a solids funnel and then rinsed with 113 g of water. The suspension was heated to 75 ° C internal temperature within one hour and then stirred at 75 ° C for 3 hours. It was then cooled over a cooling ramp from 23 ° C within 5.0 hours and stirred overnight (about 18 hours) at this temperature. The suspension was filtered through a frit and washed twice with a mixture consisting of 332.3 g of spirits and 140.2 g of water washed after. Wet yield: 487.6 g. The Wet product was then dried over the weekend (> 48 hours) at 50 ° C under vacuum (<100 mbar). Yield: 351.0 g (100.29% of theory) of a colorless crystalline powder. Finerenone (I) Content: 47.92% by weight enantiomeric excess 97.84% ee Largest minor component at RT 5.86 min. 0.22% Residual solvents: EtOH 2,594% toluene 0.003%

In a manner analogous to that described in Examples 1b and 1c, the pure finerenone (I) can be prepared from this tartrate salt.

Example 3

Production of 3 batches of pure finerenone (I) in the technical laboratory, starting from 2 kg of racemate (II).

Example 3a Tartrate production (IV)

2.00 kg (5.285 mol) of racemic finerenone (II) were initially charged in 28.0 L of a mixture consisting of ethanol, toluene denatured / water = 75:25 (v / v) at room temperature (about 23 ° C.). 1.042 kg (2.907 mol) of (+) - O, O-dibenzoyl-D-tartaric acid (III) was added via a solids funnel and then denatured with 2 L of a mixture consisting of ethanol, toluene / water = 75:25 (v / v) rinsed. The suspension thus obtained was heated to 75 ° C internal temperature within 45 minutes and then stirred for 3.0 hours at this temperature. It was then cooled over a cooling ramp from 23 ° C within 5.0 hours and stirred overnight (about 16 hours) at this temperature. The suspension was filtered through a frit and washed once with 2 L of a mixture consisting of ethanol, toluene denatured / water = 75:25 (v / v) and sucked dry for 10 minutes. Wet yield: 2.69 kg. The moist product was then dried at 50 ° C. under reduced pressure (<100 mbar) to constant mass (after about 17 hours constant mass yield: 2.009 kg (~ 100% of theory) of a colorless crystalline powder

Example 3b Preparation of crude product (I)

2.006 kg of the compound (IV) prepared in Example 3a was at room temperature (about 23 ° C) in 20.0 L of a mixture consisting of ethanol, toluene denatured / water = 1: 4 (v / v) suspended (it was pH of pH = 4 measured). Subsequently, 6.05 kg of a 9.09% aqueous sodium phosphate solution were added dropwise and the pH adjusted to pH = 7.2. The mixture was stirred for about 50 minutes at 23 ° C (pH = 7.17). Subsequently, 0.65 kg of a 9.09% aqueous sodium phosphate solution was added dropwise and the pH adjusted to pH = 7.5. It was heated to 50 ° C inside temperature within one hour and stirred at this temperature for 3.0 hours. It was cooled within one hour to 22 ° C and stirred over the weekend (about 64 hours *) at this temperature. The crystals are filtered through a K800 Seitzfilterplatte and once with 1.6 L and once with 0.8 L of a mixture consisting of ethanol, toluene denatured / water = 20:80 (v / v) and twice with 1.6 L of water rewashed. Wet yield: 1.82 kg. The moist product was then dried at 50 ° C under vacuum (<100 mbar) to constant mass (about 17 hours mass constant). Yield: 0.978 kg (97.8% of theory) of a colorless crystalline powder.

*) for technical reasons was stirred over the weekend, usually sufficient 14 hours stirring time.

Example 3c Production of pure product (I)

250 g of the crude product (I) prepared in Example 3b were suspended in 5000 ml of ethanol, toluene denatured and then heated to reflux. The product went into solution. It was stirred for an hour at this temperature. The solution was filtered through a heated pressure filter (T = 85 ° C), the pressure filter then rinsed with 200 ml of ethanol, toluene denatured. The solvent was subsequently distilled off (about 4200 ml were distilled off) until a final volume of about 4 times (based on the substance used: 250 g × 4 ~ 1000 ml) was reached. It was then cooled to 4-5 ° C internal temperature (ramp: duration about 4 hours). Then one hour at 4-5 ° C internal temperature was stirred. The product was filtered off and rinsed once with 220 ml of ethanol, toluene denatured. Moisture yield: 251.2 g. The moist product was dried at 50 ° C over the weekend (> 48 h) under vacuum (<100 mbar). Yield: 223.0 g (89.2% of theory) of a colorless crystalline powder.

The following Table 4 summarizes the results of 3 campaigns starting from 2 kg racemate of Finerenone (II):

Raw product (I)

approach Use tartrate salt (IV): kg Yield: kg Yield:% of theory Approach 1 (Example 3b) 2009 0.978 97.8 Approach 2 2.025 0.985 98.5 Approach 3 2,027 0.987 98.7 approach Content (I)% by weight Purity (HPLC) Enantiomeric excess e.e. % Residual solvent Approach 1 98,10 Finerenone (I): 99.85% 98,15 Ethanol: 0.203% (Example 3a) Largest secondary connection Pollution E: 0.07% Toluene: 0.117% Approach 2 99,00 Finerenone (I): 99.83% 97.93 Ethanol: 0.110% Largest sub-connection Pollution E: 0.08% Toluene: 0.073% Approach 3 99.70 Finerenone (I): 99.84% 97.97 Ethanol: 0.118% Largest secondary connection Pollution E: 0.07% Toluene: 0.076% In all 3 approaches the (+) - O, O-dibenzoyl-D-tartaric acid content was: 0.00%

Pure product (I)

approach Crude product (I) g Yield: g Yield:% of theory Approach 1 (Example 3c) 250 223 89.2 Approach 2 250 235 94.0 Approach 3 250 226 91.8 approach Content (I)% by weight Purity (HPLC) Enantiomeric excess e.e.% Residual solvent Approach 1 (Example 3a) 99.40 Finerenone (I): 100.00 Ethanol: 0.074% 99.82% impurity E 0.08% Toluene: 0.000% Approach 2 99.80 Finerenone (I): 99.94% 100.00 Ethanol: 0.037% toluene: 0.000% Pollution E 0.08% Approach 3 99.50 Finerenone (I): 99.85% 99.92 Ethanol: 0.033% toluene: 0.000% Pollution E 0.08% In all 3 approaches, the (+) - O, O-dibenzoyl-D-tartaric acid content (III) was 0.00%

Example 4

Operational implementation of the procedure. The following examples describe the implementation of the method on an industrial scale. The results, such as yield and analysis of 2 batches Finerenone, pure (I) are tabulated below:

Example 4a Tartrate salt (IV) preparation

• Im einem1600 L Rührwerk wurde bei IT 20°C 711,0 kg Branntwein vorgelegt, anschließend kamen 300 kg Wasser, dann 80,0 kg Racemat (II) und abschließend 41,7 kg (+)-Dibenzoyl-Weinsäure (III) hinzu.
• Es wurde auf IT 75°C erwärmt und 3h nachgerührt.
• Es wurde über 5h (Rampe) auf IT 23°C abgekühlt und 16h nachgerührt
• Die Suspension wurde zum Zentrifugieren auf die Stülpzentrifuge überführt, abgeschleudert und mit einem Gemisch, bestehend aus 10,7 kg Branntwein und 4,5 kg Wasser nachgewaschen, anschließend trocken geschleudert und ausgebracht.
• Die Trocknung erfolgte in einem 300 1 Kugeltrockner bei einer Manteltemperatur von 50°C und 30 mbar. Der Abbruch der Trocknung erfolgte bei einer Innentemperatur von 45°C (Dauer ca. 6h).
• Man kühlte auf 15°C und trug das Produkt anschließend aus.

The batch size corresponded to 80 kg of racemic finerenone (II).

• In a 1600 L stirrer, 711.0 kg of spirits were initially taken at IT 20 ° C., then 300 kg of water, then 80.0 kg of racemate (II) and finally 41.7 kg of (+) - dibenzoyltartaric acid (III) were added.
• It was heated to IT 75 ° C and stirred for 3h.
• It was cooled over 5 h (ramp) to IT 23 ° C and stirred for 16 h
• The suspension was transferred to the spin-on centrifuge for centrifugation, centrifuged and washed with a mixture consisting of 10.7 kg of spirits and 4.5 kg of water, then spun dry and applied.
• The drying was carried out in a 300 1 ball dryer at a jacket temperature of 50 ° C and 30 mbar. The demolition of the drying took place at an internal temperature of 45 ° C (duration about 6 hours).
• It was cooled to 15 ° C and then carried the product out.

Example 4b Crude product (I)

• Herstellung einer Natriumphosphat-Lösung
• In einem 630 L Rührwerk wurde bei 20°C 360,0 kg VE-Wasser vorgelegt
• 36,0 kg Natriumphosphat wurde zugegeben und gelöst
• In einem 1600 L Rührwerk wurde bei 20°C 141,1 kg Branntwein vorgelegt
• Dann wurden 714,2 kg Wasser und 89,3 kg Tartrat-Salz (IV) zugegeben
• Es wurde auf eine Innentemperatur von 50°C erwärmt
• Dann wurde 295,1 kg einer Natriumphosphat-Lösung zu dosiert
• Nach 1,5 h wurde der pH-Wert durch Zugabe von 35,4 kg Natriumphosphat-Lösung auf pH=7,5 (+/-0,1) eingestellt
• Man ließ Nachrühren und kühlte über eine Rampe (3h) auf IT=22°C ab.
• Anschließend wurde bei IT=22°C nachgerührt (18h)
• In einer Vorlage wurde ein Gemisch aus 129,6 kg Wasser und 25,6 kg Branntwein hergestellt (zum Nachwaschen)
• Die Suspension wurde auf die Stülpzentrifuge auf dosiert (ca. 4 Chargen + Rest Charge) und portionsweise einmal mit dem Gemisch aus 129,6 kg Wasser und 25,6 kg Branntwein und einmal mit 288,0 kg VE-Wasser gewaschen.
• Das Produkt wurde ausgetragen und im Kugeltrockner getrocknet (TM=50°C, 30 mbar, Abbruch IT=45°C, ca. 6h)
• Man kühlte ab und trug das Produkt bei <30°C aus

The batch size corresponded to 89.3 kg tartrate salt (IV) for use

• Preparation of a sodium phosphate solution
• In a 630 L agitator was submitted at 20 ° C 360.0 kg of deionized water
• 36.0 kg of sodium phosphate was added and dissolved
• In a 1600 L agitator was submitted at 20 ° C 141.1 kg of spirits
• Then, 714.2 kg of water and 89.3 kg of tartrate salt (IV) were added
• It was heated to an internal temperature of 50 ° C
• Then, 295.1 kg of a sodium phosphate solution was metered
• After 1.5 h, the pH was adjusted to pH = 7.5 (+/- 0.1) by adding 35.4 kg of sodium phosphate solution
• Stirring was continued and the mixture was cooled to IT = 22 ° C. over a ramp (3 h).
• The mixture was then stirred at IT = 22 ° C (18h)
• In a template, a mixture of 129.6 kg of water and 25.6 kg of spirits was prepared (for washing)
• The suspension was metered onto the inverting centrifuge (about 4 batches + remainder batch) and washed in portions once with the mixture of 129.6 kg of water and 25.6 kg of spirits and once with 288.0 kg of deionised water.
• The product was discharged and dried in a tumble dryer (TM = 50 ° C., 30 mbar, termination IT = 45 ° C., approx. 6 hours)
• The mixture was cooled and the product was discharged at <30 ° C

Example 4c Reprocessing of the crude product (I)

In some cases, when the specification limit for (+) - dibenzoyl-tartaric acid (III) in the crude product is> 0.1%, it has proved to be advantageous to carry out a makeover (see Example 6) which guarantees that the limit value <0.1% is achieved reproducibly. In addition, the reworking process is virtually loss-free and generally delivers the crude product in> 95% yield.

Converted crude product (I)

• Herstellung einer Natriumphosphat-Lösung: 2,3 kg Natriumphosphat wurden bei Raumtemperatur in 147,8 kg Wasser in einer 250 L Rührvorlage gelöst
• Bei 20°C wurden in einem 630 L Rührwerk 198,8 kg Branntwein vorgelegt und 120 kg Wasser zugegeben, anschließend wurden 30 kg Rohprodukt (enthaltend (+)-Dibenzoyl-Weinsäure (III) wie in der Tabelle 5 angegeben zugesetzt.
• Es wurde auf 70°C Innentemperatur erwärmt und 30 Minuten nachgerührt.
• Bei 70°C wurden 14,1 kg der oben hergestellten Natriumphosphat-Lösung zu dosiert und ein pH-Wert von pH 8,9 (+/- 0,1) und 20 Stunden bei 70°C nachgerührt.
• Über eine Rampe wurde innerhalb 60 Minuten auf 44°C abgekühlt und 300 g Impfkristalle Finerenone, rein (I) zugegeben
• Anschließend wurde bei 200 mbar und einer maximalen Inntemperatur von 60°C ab destilliert und parallel 369 kg Wasser ins Rührwerk zu dosiert.
• Zum Schluss wurde innerhalb 1,5 Stunden auf 22°C runter gekühlt und das Produkt auf einer Drucknutsche isoliert und in 3 Portionen mit insgesamt 180 L Wasser gewaschen
• Anschließend wurde bei 50°C Manteltemperatur unter Vakuum (30 mbar) bis zur Gewichtskonstanz getrocknet.
• Man ließ auf 15°C abkühlen und trug das Produkt aus

The batch size corresponded to 30 kg crude product (I)

• Preparation of a sodium phosphate solution: 2.3 kg of sodium phosphate were dissolved at room temperature in 147.8 kg of water in a 250 L stirring mixture
• At 20.degree. C., 198.8 kg of spirits were initially charged in a 630 l stirrer and 120 kg of water were added, followed by the addition of 30 kg of crude product (containing (+) - dibenzoyltartaric acid (III) as indicated in Table 5).
• It was heated to 70 ° C internal temperature and stirred for 30 minutes.
• At 70 ° C., 14.1 kg of the sodium phosphate solution prepared above were metered in and a pH of 8.9 (+/- 0.1) was stirred in and the mixture was stirred at 70 ° C. for 20 hours.
• Over a ramp was cooled within 60 minutes to 44 ° C and 300 g of seed crystals Finerenone, pure (I) was added
• The mixture was then distilled off at 200 mbar and a maximum internal temperature of 60 ° C. and 369 kg of water were added in parallel to the stirrer.
• Finally, it was cooled down to 22 ° C. within 1.5 hours and the product was isolated on a pressure filter and washed in 3 portions with a total of 180 l of water
• Subsequently, at 50 ° C jacket temperature under vacuum (30 mbar) was dried to constant weight.
• It was allowed to cool to 15 ° C and carried out the product

Example 4d Pure product (I)

• In einem 250 L Rührwerk wurden 13 kg umgearbeitetes Rohprodukt (I) in 184,9 kg Branntwein bei 20°C vorgelegt und das Rührwerk zuvor inertisiert
• Die Lösung wurde auf 80°C Manteltemperatur erhitzt und 30 Minuten bei 78°C nachgerührt (dabei geht das Produkt in Lösung).
• Die Lösung wurde über eine 0,65 um Filterkerze (PP-Kerze Sartorius) filtriert (GMP-Filtration) und das Filtrat in ein 630L Rührwerk überführt.
• Es wurde mit 18,5 kg Branntwein nachgewaschen
• Dieses wurde in 2 Teilportionen (2 mal 13 kg Produkt) wiederholt und die Lösungen vereinigt
• Es wurde zu einem finalen Füllstand von ca. 130 L bei Normaldruck abdestillert (in zwei Portionen, Manteltemperatur: 104°C, Dauer ca. 6 Stunden)
• Die Lösung wurde über eine lineare Temperaturrampe über 4 Stunden auf 0°C runtergekühlt und anschließend wurde eine Stunde nach gerührt.
• Die Produkt-Suspension wurde über eine Drucknutsche isoliert und mit 45,9 kg Branntwein gewaschen
• Das Feuchtprodukt wurde anschließend unter Vakuum (30 mbar) bei 50°C bis zur Gewichtkonstanz (ca. 12 h) getrocknet. Es wurde auf 15°C abgekühlt und das Produkt ausgebracht.

The batch size corresponded to 26 kg (2 times 13 kg) of processed crude product (I)

• In a 250 L stirrer 13 kg of reacted crude product (I) were presented in 184.9 kg of brandy at 20 ° C and the agitator previously inertized
• The solution was heated to 80 ° C jacket temperature and stirred for 30 minutes at 78 ° C (the product goes into solution).
• The solution was filtered through a 0.65 μm filter candle (PP candle Sartorius) (GMP filtration) and the filtrate transferred to a 630 L stirrer.
• It was washed with 18.5 kg of brandy
• This was repeated in 2 portions (2 x 13 kg of product) and the solutions combined
• It was distilled off to a final level of about 130 L at atmospheric pressure (in two portions, jacket temperature: 104 ° C, duration about 6 hours)
• The solution was cooled down to 0 ° C over a linear temperature ramp over 4 hours and then stirred for one hour.
• The product suspension was isolated via a pressure filter and washed with 45.9 kg of spirits
• The moist product was subsequently dried under reduced pressure (30 mbar) at 50 ° C. to constant weight (about 12 h). It was cooled to 15 ° C and the product was discharged.

Overview of the yield and analytical results of 3 operational batches for the preparation of pure finerenone (I) is shown in Table 5

Tartrate salt (IV)

Raw product (I)

approach Use tartrate salt (IV) kg Yield (I, crude): kg Yield:% of theory Approach 1 (Example 4b) 89.3 36.6 80 Approach 2 89.3 44.2 96 Approach 3 89.3 45.7 99 approach Content (I)% by weight Purity (HPLC) Enantiomeric excess e.e.% Residual solvent Approach 1 (Example 4b) 98.5 Finerenone (I): 98.8 Ethanol: 0.098% 99.71% Toluene: 0.048% Pollution E: 0.08% Sum of all organic minor components: 0.29% (+) - Dibenzoyl-tartaric acid: 0.71% Approach 2 98.2 Finerenone (I): 97.70% 98.9 Ethanol: 0.151% Pollution E: 0.08% Toluene: 0.088% Sum of all organic minor components: 0.30% (+) - dibenzoyl-tartaric acid: 0.39% Approach 3 100 Finerenone (I): 98.7 Ethanol: 0.102% 99.76% impurity E: 0.07% Toluene: 0.066% Sum of all organic minor components: 0.0.24% (+) - Dibenzoyl-tartaric acid: 0.46%

Crude product (I) after reworking

approach Use (I): kg Yield (I): kg Yield:% of theory Approach 1 (Example 4c) 30 29.8 99.33 Approach 2 30 29.8 99.33 approach Content (I)% by weight Purity (HPLC) Enantiomeric excess e.e.% Residual solvent Approach 1 (Example 4c) 99.6 Finerenone (I): 98.8 Ethanol: n.n. 99.70% Toluene: n.n. (+) - dibenzoyl-tartaric acid: <0.05% Largest minor component impurity E: 0.08% Sum of all organic minor components: 0.3% Approach 2 99.6 Finerenone (I): 98.8 Ethanol: n.n. 99.70% Toluene: n.n. (+) - dibenzoyl-tartaric acid: <0.05% Largest minor component impurity E: 0.08% Sum of all organic minor components: 0.3%

Pure Product, Finerenone, Pure (I)

approach Use kg Yield: kg Yield:% of theory Approach 1 (Example 4d) 26 23.1 88.85 Approach 2 26 22.9 88,08 approach Content (I)% by weight Purity (HPLC) Enantiomeric excess e.e.% Residual solvent Approach 1 (Example 4d) 100 Finerenone (I): 100 Ethanol: 0.044 99.8% Toluene: 0.00 Sum of all organic minor components: 0.2% Water: <0.2 Largest minor component impurity E: 0.08% (+) - Dibenzoyl-tartaric acid: <0.05 Approach 2 100 Finerenone (I): 100 Ethanol: 0.063 99.8% Toluene: 0.00 Sum of all organic minor components: 0.2% Water: <0.2 Largest minor component impurity E: 0.08% (+) - dibenzoyl-tartaric acid: <0.05%

Example 5

To release the crude Finerenone (I), several variants are analogous to the procedure of Example 1b. The aim was to keep the proportion of (+) - O, O-dibenzoyl-D-tartaric acid (III) in the crude product as small as possible (0.15% and less). The final pH after addition of the sodium phosphate solution, temperature, metering time of the sodium phosphate solution and stirring time were varied in detail and the influence on the content of (+) - O, O-dibenzoyl-D-tartaric acid in the crude product was investigated.

Batch size: 100 g of tartrate salt (IV) in 158.0 g of brandy and 799.8 g of water
Analytical data on tartrate salt (IV): Finerenone (I) 48.05% by weight (HPLC) enantiomeric excess 97.71% ee Largest unknown minor component at Rt 5.606 min. 0.28% Residual solvents: EtOH 2,576% toluene 0.006%

Table 6 below summarizes the results: Table 6 approach PH value Amount Na ₃ PO ₄ - solution (g) (100g / 1L water) T (° C) Dosing time (min.) Stirring time (min.) Purity Finerenone (I) HPLC (%) Yield (% of theory) Proportion of (+) - di-benzoyl-tartaric acid (% by weight) 1 7.5 400 50 30 180 99.17 97.2 0.0996 2 7.5 400 60 30 180 99.74 97.2 .1101 3 8.0 444.9 50 30 180 99.86 97.0 0.0986 4 8.5 467.7 50 30 180 99.73 96.6 .1298 5 9.0 480.3 50 30 180 99.85 97.4 .1027 6 7.5 400 50 30 60 99.86 96.8 .1010 7 7.5 400 50 30 300 99.87 97.2 .1058 8th 7.5 400 50 8th 180 99.73 97.6 0.1294

Example 6 MAKEOVER method Example 6a Reprocessed crude product: Reduction of fraction (+) - O, O-dibenzoyl-D-tartaric acid <0.1 %

This experiment served to demonstrate the robustness of the remodeling process by deliberately using a batch with increased (+) - O, O-dibenzoyl-D-tartaric acid (III) content.

A crude product which according to the analysis still contained 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III) was used for reworking Finerenone, raw (I) Purity: 99.67% area (HPLC); Content: 98.69% by weight (+) - O, O-dibenzoyl-D-tartaric acid 0.77% Largest minor component contamination E 0.07%

Reprocessing of the crude product: Reduction of the proportion (+) - O, O-dibenzoyl-D-tartaric acid (III) <0.1%

A crude product which according to the analysis still contains 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III) was used for reworking. The procedure was as follows:
150 g of crude product (I) (containing 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III)) were added to 600 g of water and 953.9 g of brandy and heated to 70 ° C. Within an hour everything went into solution. The mixture is then stirred at 70 ° C for 30 minutes. The pH is pH = 5.0. The pH was adjusted to pH = 8.5 by adding 44.6 g of an aqueous sodium phosphate solution (15 g of sodium phosphate to 985 g of water) and then stirred at 70 ° C. for 2 hours. Within 30 minutes, cooled to 53 ° C and seeded with pure material (seed crystals) on. The mixture was then stirred at 50-52 ° C for 30 minutes. At 200 to 155 mbar and an internal temperature, the ethanol was almost completely distilled off and metered in parallel to 1845 ml of water (the level was kept constant: from distilled amount = added amount of water). The heating was switched off and the suspension was stirred overnight at 23 ° C. The crystals were filtered through a frit and washed three times with 300 ml of water. Wet yield: 218.9 g. The moist product was dried at 50 ° C over the weekend (> 48 hours) in vacuo (<100 mbar). Yield: 146.7 g (97.8% of theory) Finerenone (I) Purity: 99.87 area (HPLC); Content: 100.3% by weight enantiomeric excess 97.87% ee (+) - O, O-dibenzoyl-D-tartaric acid 0.00% Largest minor component contamination E 0.07% Residual solvents: EtOH 0.286%

Example 6b Demonstration of stability, stirring at 70 ° C for 20 h Reprocessing of the crude product: Reduction of the proportion (+) - O, O-dibenzoyl-D-tartaric acid (III) ≤ 0.1%

A crude product which according to the analysis still contains 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III) was used for reworking. The procedure was as follows:
150 g of crude product (I) (containing 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III)) were added to 600 g of water and 953.9 g of brandy and heated to 70 ° C. Within an hour everything went into solution. The mixture is then stirred at 70 ° C for 30 minutes. The pH is pH = 5.0. The pH was adjusted to pH = 8.5 by adding 45.2 g of an aqueous sodium phosphate solution (15 g of sodium phosphate to 985 g of water) and then stirred at 70 ° C. for 20 hours. Within 30 minutes, cooled to 53 ° C and seeded with pure material (seed crystals) on. The mixture was then stirred at 50-52 ° C for 30 minutes. At 200 to 155 mbar and an internal temperature, the ethanol was almost completely distilled off and metered in parallel to 1845 ml of water (the level was kept constant: from distilled amount = added amount of water). The heating was switched off and the suspension was stirred overnight at 23 ° C. The crystals were filtered through a frit and washed three times with 300 ml of water. Wet yield: 194.3 g. The moist product was dried at 50 ° C overnight (about 16 hours) in vacuo (<100 mbar). Yield: 143.1 g (95.4% of theory) Finerenone (I) Purity: 99.86 area (HPLC); Content: 101.3% by weight enantiomeric excess 97.85% ee (+) - O, O-dibenzoyl-D-tartaric acid 0.00% area (0.024 wt%) Largest minor component contamination E 0.07% Residual solvents: EtOH 0.128%

Example 6c Reprocessing of the crude product: Reduction of the proportion (+) - O, O-dibenzoyl-D-tartaric acid (III) <0.1%. Back-titration of the pH to pH 7.0 with sodium dihydrogen phosphate

A crude product which according to the analysis still contains 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III) was used for reworking. The procedure was as follows:
375.0 g of crude product (I) (containing 0.77% (+) - O, O-dibenzoyl-D-tartaric acid (III)) were added to 1500 g of water and 2384.8 g of spirits and heated to 70 ° C. Within an hour everything went into solution. The mixture is then stirred at 70 ° C for 30 minutes. The pH is pH = 4.9. The pH was adjusted to pH = 8.5 by addition of 101.4 g of an aqueous sodium phosphate solution (15 g of sodium phosphate to 985 g of water) and then stirred at 70 ° C. for 20 hours. Subsequently, the pH was adjusted to pH = 7 with a sodium dihydrogen phosphate solution (50 g sodium dihydrogen phosphate 50 g in 200 ml water). Within 30 minutes, cooled to 53 ° C and seeded with pure material (seed crystals) on. Then it was 30 minutes stirred at 50-52 ° C. At 200 to 155 mbar and an internal temperature, the ethanol was almost completely distilled off and in parallel 4610 ml of water to be metered (the level was kept constant: from distilled amount = added amount of water). It was then cooled to 23 ° C within 90 minutes. Then over the weekend (about 70 h) at 22 ° C was stirred. The crystals were filtered through a frit and washed three times with 750 ml of water. Wet yield: 402.3 g. The moist product was dried at 50 ° C overnight (about 16 hours) in vacuo (<100 mbar). Yield: 336.6 g (89.76% of theory) Finerenone, raw (I) Purity: 99.84 area (HPLC); Content: 99.2% by weight enantiomeric excess 98.02% ee (+) - O, O-dibenzoyl-D-tartaric acid 0.00% area (0.0068% by weight) Largest minor component contamination E 0.07% Residual solvents: EtOH 0.107% toluene 0.001%

Example 6d Final crystallization of the batch from example 6c

80.0 g of the crude product (I) prepared in Example 6c were suspended in 1600 ml of ethanol, toluene denatured and then heated to reflux. The product went into solution. It was stirred for an hour at this temperature. The solution was filtered through a heated pressure filter (T = 75 ° C), then rinsed with 100 ml of ethanol, toluene denatured. It was then the solvent under vacuum (jacket temperature 45-47 ° C) as far as carefully distilled off until a final volume of about 5 times (bzg on substance used: 80g x 5 ~ 400 ml) was reached. The mixture was then cooled within one hour to 2 ° C internal temperature and stirred for about 1 h at this temperature. The product was filtered off and washed once with 80 ml of ethanol, toluene denatured. Wet yield: 83.3 g. The moist product was dried at 50 ° C overnight for about 16 h) under vacuum (<100 mbar). Yield: 71.4 g (89.3% of theory) of a colorless crystalline powder, fine needle crystals.

Analytical results:

Finerenone (I) Purity: 99.82 area (HPLC); Content: 98.7% by weight enantiomeric excess 99.87% e.e. Largest minor component contamination E 0.08% Residual solvents: EtOH 0.489% toluene 0.005%

Example 7 Isolation of Finerenone Enantiomer (Ia) Example 7a Preparation of (-) - O, O-Dibenzoyl-L-tartaric tartrate salt

187.2 g racemate (II) were initially charged at room temperature and then added to 1662.5 g of spirits. Then 485.5 g of water was added. 97.5 g% (-) - O, O-dibenzoyl-L-tartaric acid (IIIa) were added via a solids funnel and then rinsed with 156.0 g of water. The suspension was heated to 75 ° C internal temperature within one hour and then stirred at 75 ° C for 3 hours. It was then cooled over a cooling ramp from 23 ° C within 5.0 hours and stirred overnight (about 18 hours) at this temperature. The suspension was filtered off through a frit and washed twice with a mixture consisting of 178 g of spirits and 75 g of water washed after. Moisture yield: 255.4 g. The moist product was then dried overnight (about 16 hours) at 50 ° C under vacuum (<100 mbar). Yield: 188.6 g (100.73% of theory) of a colorless crystalline powder. The mother liquor and washing solution were combined (about 3200 ml yellowish solution, pH = 4.6) and from this the finerenone, crude (I) isolated (Example 7b) Finerenone enantiomer (Ia) 49.3% by weight (HPLC) enantiomeric excess 97.35% ee Residual solvents: EtOH 1,847% toluene 0.00%

In an analogous manner, as described in Example 1b and 1c from this tartrate salt, the enantiomer of finerenones (Ia) can be prepared.

Example 7b Isolation of finerenone, crude (I) from the mother liquor

The combined mother liquor and wash solution from Example 7a (about 3200 ml yellowish solution, pH = 4.6) was adjusted to pH = 7 at room temperature by adding 43.3 g of an aqueous sodium phosphate solution (100 g dissolved in 1 L water) , 6 set. Subsequently, under reduced pressure (85 to 65 mbar, 38 to 20 ° C internal temperature), the spirits were largely distilled off and reduced to a final volume of about 0.8 L. It was cooled to room temperature and the precipitated suspension was stirred for 2 hours at 22 ° C. The suspension was filtered off and washed twice with 150 ml of water each time. Wet yield: 159.1 g. The moist product was dried at 50 ° C overnight (about 16 h) under vacuum (<100 mbar). Yield: 86.3 g (92.2% of theory based on racemate (II) used in Example 7a). Finerenone (I) Purity: 99.48% area (HPLC); Content: 99.39% by weight enantiomeric excess 98.14% ee Largest minor component contamination E 0.13% (-) - O, O-dibenzoyl-L-tartaric acid 0.14% (0.05% by weight)

In an analogous manner, as described in Example 1c, from this crude product Finerenone (I) can be prepared in pure form.

Example 8 Example 8a Isolation of the missing enantiomer (Ia) from the mother liquor

The combined mother liquor and washing solution from example 1a (about 3750 ml yellowish solution, pH = 4.5) was adjusted to pH = 7 at room temperature by adding 101.1 g of an aqueous sodium phosphate solution (100 g dissolved in 1 L water) , 5 set. Subsequently, the spirits were distilled off under reduced pressure (85 to 65 mbar, 38 to 20 ° C internal temperature) and reduced to a final volume of about 0.85 L. It was cooled to room temperature and the precipitated suspension, stirred over the weekend (> 48 hours), then stirred for a further 2 hours at 22 ° C. The Suspension was filtered off and washed twice with 200 ml of water. Wet yield: 139.1 g. The moist product was dried at 50 ° C overnight (about 16 h) under vacuum (<100 mbar). Yield: 103.1 g (82.48% of theory, based on racemate (II) used in Example 1a). Finerenone enantiomer (Ia) Purity: 99.75% area (HPLC); Content: 99.2% by weight enantiomeric excess 99.34% ee Largest minor component contamination E 0.12% (+) - O, O-dibenzoyl-D-tartaric acid 0.14% (0.05% by weight) water 0.102%

Example 8b Operational Approach to Isolate the Finerenone Enantiomer (Ia)

• Herstellung einer Natriumphosphat-Lösung: 7,3 kg Natriumphosphat wurden in 73,1 kg Wasser bei 20°C gelöst
• In einem 1600 L Rührwerk wurden 1165 kg Mutterlauge (inclusive Waschlösung) bei 20°C vorgelegt und mit 28 kg der oben hergestellten Natriumphosphat-Lösung der pH auf 7,5 (+/-0,1) eingestellt
• Es wurde 0,25 h nachgerührt und anschließend unter Vakuum (65 mbar, IT ca. 22°C) Branntwein bis auf einen Füllstand von ca. 310 L abdestilliert
• Anschließend wurde 2 h bei 20°C nachgerührt und die Suspension über eine Stülpzentrifuge isoliert, wobei jeweils mit 20 kg Wasser gewaschen wurde.
• Das Feuchtprodukt wurde in einem Kugeltrockner bei 50°C unter Vakuum getrocknet (30 mbar; ca. 6 h)
• Es wurde auf 15°C abgekühlt und das Produkt ausgebracht

A combined mother liquor and washing solution from Example 4 (tartrate production on an industrial scale) was worked up as follows: amount about 1165 kg solution

• Preparation of a sodium phosphate solution: 7.3 kg of sodium phosphate were dissolved in 73.1 kg of water at 20 ° C.
• In a 1600 L stirrer, 1165 kg of mother liquor (including washing solution) were initially charged at 20 ° C. and adjusted to 7.5 (+/- 0.1) with 28 kg of the sodium phosphate solution prepared above
• The mixture was stirred for 0.25 h and then distilled off under vacuum (65 mbar, IT about 22 ° C) spirits to a level of about 310 L.
• The mixture was then stirred for 2 h at 20 ° C and the suspension was isolated on a slip-on centrifuge, in each case with 20 kg of water was washed.
• The moist product was dried in a ball dryer at 50 ° C. under reduced pressure (30 mbar, approximately 6 h).
• It was cooled to 15 ° C and the product was discharged

Analytical data of the mother liquor used (including rinsing solution) to approach 1

Finerenone enantiomer (Ia) 92.4% (HPLC) enantiomeric excess 95.92 Largest minor component contamination E 0.26% (+) - O, O-dibenzoyl-D-tartaric acid 5.38% (HPLC) Residual solvent ethanol 0.319% toluene 0.001%

Analytical data of the mother liquor used (including rinsing solution) to approach 2

Finerenone enantiomer (Ia) 92.03% enantiomeric excess 99.03 Largest minor component contamination E 0.15% (+) - O, O-dibenzoyl-D-tartaric acid 5.94% Residual solvent ethanol 0.177% toluene 0.001% approach Use kg Yield: kg Yield:% of theory Approach 1 ~ 1165 mother liquor (including rinsing solution) 38.2 96 Approach 2 ~ 1165 mother liquor (including rinsing solution) 37.1 93

Analytics Data Approach 1

Finerenone enantiomer (Ia) Purity: 99.71% enantiomeric excess 96.56% e.e. Largest minor component contamination E 0.106% (+) - O, O-dibenzoyl-D-tartaric acid 0.081%

Analytics Data Approach 2

Finerenone enantiomer (Ia) Purity: 99.446% enantiomeric excess 99.5% e.e. Largest minor component contamination E 0.107% (+) - O, O-dibenzoyl-D-tartaric acid 0.33%

Example 9

Examples of other tartaric acid derivatives and other solvents

Example 9a (+) - O, O-di-p-anisoyl-D-tartaric acid

100 mg of racemate were dissolved with 111 mg of (+) - O, O-di-p-anisoyl-D-tartaric acid in 5 ml of dichloromethane and allowed to stand. After some time, the diastereomer salt precipitated. This was filtered off and the enantiomeric excess was measured. The measurement gave an enantiomeric excess of 68% e.e. in favor of (Ia)

Example 9b (- ) - O, O'-di-p-toluyl-L-tartaric acid

100 mg of racemate were added with 0.55 eq. (-) - Dissolved O, O-di-p-toluyl-L-tartaric acid in 4 ml of solvent and allowed to stand. After some time, the diastereomer salt precipitated. This was filtered off and the enantiomeric excess was measured. The measurement revealed an enantiomeric excess of y% ee in favor of (Ia). Table 7 below summarizes the results Table 7: 4 ml of solvent / solvent mixture Enantiomeric excess ee% (Ia) n-propanol / water 80:20 85.35 n-pentanol / water 90:10 89,10 Methanol / water 80:20 84.47 methanol 93.18 Isopropanol / water 80:20 81.20 Isobutanol / water 90:10 79.25 Ethylene glycol / water 80:20 93.68 ethylene glycol 68,50 Ethanol / water 80:20 85.87 ethanol 85.96 2-butanol / water 80:20 83.92 1-butanol / water 90:10 88.93

Example 9c (+) - O, O'-dibenzoyl-D-tartaric acid

100 mg of racemate were added with 0.55 eq. (+) - O, O'-dibenzoyl-D-tartaric acid dissolved in 4 ml of solvent and allowed to stand. After some time, the diastereomer salt precipitated. This was filtered off and the enantiomeric excess was measured. The measurement showed an enantiomeric excess of y% ee in favor of (I). Table 8 below summarizes the results Table 8: 4 ml solvent / solvent mixture Enantiomeric excess ee% (I) n-propanol / water 80:20 94,01 n-pentanol / water 90:10 94.59 Methanol / water 80:20 89.09 methanol 91.21 Isopropanol / water 80:20 90.92 Isobutanol / water 90:10 85.42 ethylglycol 92.08 Ethanol / water 80:20 94.64 ethanol 93.64 Cyclohexanol / water 90:10 84.33 Benzyl alcohol / water 90:10 88.83 2-butanol / water 80:20 92.49 1-pentanol 80,99 1-butanol / water 90:10 94.02

Claims (15)

Racemate cleavage of (II)

in (Ia) and / or (I)

with chiral substituted tartaric acid esters of the general formulas (IIIa) or (IIIb)

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic. Process for the preparation of (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide of the formula ( I)

by racemate resolution of (II)

with a chiral substituted tartaric acid ester of the formula (IIIa)

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic. A method according to claim 1 or 2, characterized in that the resolution is carried out in ethanol / water mixture. Method according to one of claims 1 to 3, characterized in that the racemate resolution takes place at a temperature in the range of 60 to 80 ° C. Method according to one of claims 1 to 4, characterized in that Ar is phenyl. Method according to one of claims 1 to 5, characterized in that dibenzoyltartaric acid (V)

used for racemate separation. Process according to one of Claims 1 to 6, characterized in that the precipitated diastereomer salt (IVa), (IVb), (IVc) and / or (IVd) are isolated. Process according to one of Claims 1 to 7, characterized in that the diastereomer salt is treated with a base and the solvent is removed. Method according to one of claims 1 to 8, characterized in that potassium hydroxide, potassium phosphate or sodium phosphate are used as the base. Method according to one of claims 1 to 9 wherein the racemate

with dibenzoyltartaric acid of the formula (V)

in a spirits / water mixture to the diastereomer salt (VI)

implemented, and then Finerenone (I)

sodium phosphate is also released in a spirits / water mixture. Diastereomer salts according to the formula

or

wherein Ar is an unsubstituted or substituted aromatic or heteroaromatic. Diastereomeric salt according to claim 11, characterized in that Ar represents

where * represents the point of attachment. Diastereomeric salt according to claim 11 or 12, characterized in that Ar is phenyl. Finerenone (I) having a dibenzoyltartaric acid content ≤ 0.15% obtained by reacting the racemate (II)

with dibenzoyltartaric acid of the formula (V)

in a spirits / water mixture to the diastereomer salt (VI)

and then Finerenone (I)

also releases sodium phosphate in a spirits / water mixture and then pure finerenone crystallized with a dibenzoyltartaric ≤ 0.15%. Finerenones (I) having a dibenzoyltartaric acid content ≤ 0.1% obtained by a process according to claim 14.